The objective of this research program is to investigate the anatomic pattern of communication of the prefrontal cortex with other cortical and subcortical brain regions. The specific purpose is to examine the connectional organization of those prefrontal cortices which are considered limbic. The rationale is based on the importance of the prefrontal cortex, in general, and the limbic system, in particular, for memory, cognition and emotion. The choice of a primate is predicated by the unique set of connections between the phylogenetically older limbic system and the more recently evolved isocortex in primates. Damage to the limbic system in primates disrupts a series of higher order functions previously associated exclusively with the neocortices. Our previous work suggests that the degree of cortical architectonic differentiation is central to the pattern of connections between prefrontal and sensory association cortices, and seems to be also associated with several other cortical organizational features. This hypothesis will be tested further by: investigating the sources of cortical and subcortical projections to the largely unexplored medial and orbital frontal limbic regions; comparing the sources of afferent projections to medial and orbital limbic regions; and studying the regional distribution of acetylcholinesterase, cytochrome oxidase, and myelin to determine the chemical composition of the projection zones. Connections will be studied using both horseradish peroxidase and fluorescent dyes to label the neurons of origin. Limbic cortices have widespread cortical and subcortical connections, suggesting that they may exercise a tonic influence on the entire brain. These studies may have important implications for the processes underlying the disruption of higher order functions following traumatic or degenerative insult to the limbic cortices, and for the development of the cortex in phylogeny.